scholarly journals The Influence of Age, Sex and Exercise on Autophagy, Mitophagy and Lysosome Biogenesis in Skeletal Muscle

2021 ◽  
Author(s):  
Matthew Triolo ◽  
Ashley N. Oliveria ◽  
Rita Kumari ◽  
David A. Hood
Keyword(s):  
Skeletal Muscle ◽  
Acute Exercise ◽  
Young Male ◽  
Young Female ◽  
The Other ◽  
Male Mice ◽  
Mitochondrial Content ◽  
Female Mice ◽  
Biological Sex ◽  
Lysosome Biogenesis

Abstract BackgroundAging decreases skeletal muscle mass and quality. Maintenance of healthy muscle is regulated by a balance between protein and organellar synthesis and their degradation. The autophagy lysosome system is responsible for the selective degradation of protein aggregates and organelles, such as mitochondria (i.e., mitophagy). Little data exist on the independent and combined influence of age, biological sex and exercise on the autophagy system and lysosome biogenesis. The purpose of this study was to characterize sex differences in autophagy and lysosome biogenesis in young and aged muscle, and to determine if acute exercise influences these processes.MethodsYoung (4-6 months) and aged (22-24 months) male and female mice, were assigned to a sedentary, or an acute exercise group. Mitochondrial content, the autophagy-lysosome system and mitophagy were measured via protein analysis. A Tfeb-promoter-construct was utilized to examine Tfeb transcription, and nuclear-cytosolic fractions allowed us to examine Tfeb localization in sedentary and exercised muscle with age and sex.ResultsOur results indicate that female mice, both young and old, had more mitochondrial protein than age-matched males, and mitochondrial content was only reduced with age in the male cohort. Although young female mice had a greater abundance of autophagy, mitophagy and lysosome proteins than young males, we measured increases with age irrespective of sex. Interestingly, young sedentary female mice had indices of greater autophagosomal turnover than male counterparts. Exhaustive exercise was able to stimulate autophagic clearance in young male mice, but not in the other groups. Similarly, nuclear Tfeb protein was enhanced to a greater extent in young male than in young female mice following exercise, but no changes were observed in aged mice. Finally, Tfeb-promoter activity was upregulated following exercise in both young and aged muscle.ConclusionsThe present study demonstrates that biological sex influences mitochondrial homeostasis, the autophagy-lysosome system and mitophagy in skeletal muscle with age. Further, our data suggest that young male mice have a more profound ability to activate these processes with exercise than in the other groups. Ultimately, this may contribute to a greater remodeling of muscle in response to exercise training in males.

Abstract 113: Regulatory T Cells Contribute to Sexual Dimorphic Outcomes After Acute Ischemic Brain Injury

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Zeyu Sun ◽  
Wei Su ◽  
Ligen Shi ◽  
Jie Chen ◽  
Xiaoming Hu
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Immune Cell ◽  
Infarct Volume ◽  
Young Male ◽  
Young Female ◽  
Male Mice ◽  
Stroke Outcomes ◽  
Female Mice ◽  
Ifn Γ

Introduction: The contribution of CD4 + Foxp3 + regulatory T cells (Treg) to acute stroke outcomes has been controversially reported in young male murine models of stroke, their effects in female stroke mice, however, are not characterized. This study explored the sexual dimorphisms in Treg and its contribution to acute stroke outcomes. Methods: Cerebral ischemia was induced by 60 min tMCAO in male or female (Young: 10-week, aged: 15-month) wild type (WT) mice and DTR mice expressing the diphtheria toxin (DT) receptor under the control of Foxp3 promoter. Tregs depletion was achieved by DT injection in DTR mice for 3 days prior to tMCAO. Infarct volume, sensorimotor functions and peripheral immune cell populations were assessed up to 5d after stroke. For RNA sequencing analysis, Tregs were sorted from blood of male or female DTR mice at 5d after sham or tMCAO surgery. Results: Young Treg competent (WT mice or DTR mice without DT) female mice exhibited significantly reduced infarct volume, as assessed by MRI T2 scanning and MAP2 staining, and greatly improved sensorimotor functions (rotarod test and adhesive removal test) compared to age- and genotype-matched male mice (n=8/group) 5d after tMCAO. Treg depletion deprived the neuroprotection in young female, while showed no significant effect on young male or aged female mice (n=8/group). RNA-seq analysis showed that IFN-γ signaling was downregulated in female Treg while upregulated in male Treg, suggesting a sexual difference in Treg-mediated immune response after stroke. Flow cytometry revealed ameliorated immune cell activation in blood and brain in female vs male mice 5d after stroke. Furthermore, Treg were isolated from young female, young male, aged female or female mice subjected to ovariectomy, and adoptively transferred (1 million cell/animal, iv) to young male mice 1 hour after tMCAO. Only young female Treg significantly reduced the infarct volume and improved sensorimotor functions compared to other treatment groups (n=7-8/group). Conclusion: Treg contribute to the neuroprotection in young female vs male in an age- and hormone-dependent manner. Transcriptomic analysis uncovered sexual differences in an IFN-γ centered regulatory pathways in Tregs, which keep post-stroke immune responses in check.

P–060 Dose- dependent mitigation of lead acetate toxicity in males on embryo development in female mice

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
P Dolati ◽  
M J Zamiri ◽  
A Akhlaghi ◽  
Z Jahromi
Keyword(s):  
Adverse Effects ◽  
Embryonic Development ◽  
Embryo Development ◽  
Lead Acetate ◽  
Endocrine System ◽  
Cell Number ◽  
The Other ◽  
Control Group ◽  
Male Mice ◽  
Female Mice

Abstract Study question Does quercetin (75 or 100 mg/kg BW/day) co-administration with lead acetate to male mice affects embryonic development in female mice? Summary answer The low-dose quercetin (75 mg/kg BW/day) ameliorated the adverse effects of lead acetate on mouse embryogenesis. What is known already Lead causes male infertility by impacting on endocrine system and spermatogenesis, and may exert undesirable effects on the offspring. The currently approved treatment for lead poisoning is the use of chelating agents, which form an insoluble complex with lead and shield it from biological targets; thus, reducing its toxicity. One of the main mechanisms of lead-induced toxicity is oxidative stress, and it has been reported that natural antioxidants can reduce the heavy metals toxicity. The aim of the present study was to examine the protective effects of quercetin on the toxicity induced by lead acetate on the embryogenesis in mice. Study design, size, duration Sexually mature (eight-week-old) NMRI male mice (n = 24) were randomly divided into four groups (n = 6 per group) receiving (i) distilled water (control group); (ii) lead acetate (150 mg/kg BW/day) dissolved in deionized water (LA); (iii) lead acetate (150 mg/kg BW/day) + quercetin (75 mg/kg BW/day) (LQ75); (IV) lead acetate (150 mg/kg BW/day) + quercetin (100 mg/kg BW/day) (LQ100). Treatments were applied daily as oral gavages for one cycle of the seminiferous epithelium (35 days). Participants/materials, setting, methods At the end of treatment administration, the males were joined with super-ovulated females, and the retrieved zygotes were cultured for evaluation of the embryo development (at 2-cell, 4-cell, 8-cell, and blastocyst stages), and blastocyst cell number using differential staining (propidium iodide and bisbenzimide). After incubation of capacitated sperm with oocytes, an ultraviolet light microscope was used following 3 min incubation with 25 µg⁄mL bisbenzamide solution for fertilization assessment. Main results and the role of chance Lead acetate (LA) treatment of male mice decreased the 2-cell stage compared with the control group (P > 0.05). There was no difference between control and LQ75, and between LA and LQ100. The other stages of embryonic development were not significantly affected by the treatment. Overall, early embryonic development in the control and LQ75 mice were better than LQ100 and LA mice. The number of cells in the trophectoderm and inner-cell mass were not affected by treatments. However, the total blastocyst cell number in the control was higher than in the other groups; there was no significant difference between LQ100, LQ75 and LA groups. Fertilization rate was not affected by the treatments (P < 0.05). Quercetin acts as a potent antioxidant at low doses, but at high doses exerts a pro-oxidant action. According to previous reports, higher concentrations of quercetin increased apoptosis and necrosis while decreasing the activities of the antioxidant enzymes. Also, it has been suggested that quercetin might disrupt the endocrine system and interfere with Sertoli cell function and sperm motility. Limitations, reasons for caution A limitation of this study is narrow dose selection; more studies are needed to determine the effective dose of quercetin in ameliorating the lead toxicity. There are also side effects of lead-quercetin chelates such as metal redistribution, essential metal loss, accumulation and persistency in intracellular sites, and peroxidation. Wider implications of the findings: Lead administration adversely impacted on the embryogenesis; on the other hand, paternal quercetin co-administration somewhat ameliorated the adverse effects of lead on mice embryogenesis. Trial registration number Not applicable

scholarly journals Changes in Retinal Structure and Ultrastructure in the Aged Mice Correlate With Differences in the Expression of Selected Retinal miRNAs

2021 ◽  
Vol 11 ◽  
Author(s):  
Anca Hermenean ◽  
Maria Consiglia Trotta ◽  
Sami Gharbia ◽  
Andrei Gelu Hermenean ◽  
Victor Eduard Peteu ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Amorphous Materials ◽  
Retinal Pigment ◽  
Ultrastructural Changes ◽  
Male Mice ◽  
Bruch's Membrane ◽  
Bruch’S Membrane ◽  
Female Mice ◽  
Biological Sex ◽  
Age Related

Age and gender are two important factors that may influence the function and structure of the retina and its susceptibility to retinal diseases. The aim of this study was to delineate the influence that biological sex and age exert on the retinal structural and ultrastructural changes in mice and to identify the age-related miRNA dysregulation profiles in the retina by gender. Experiments were undertaken on male and female Balb/c aged 24 months (approximately 75–85 years in humans) compared to the control (3 months). The retinas were analyzed by histology, transmission electron microscopy, and age-related miRNA expression profile analysis. Retinas of both sexes showed a steady decline in retinal thickness as follows: photoreceptor (PS) and outer layers (p < 0.01 for the aged male vs. control; p < 0.05 for the aged female vs. control); the inner retinal layers were significantly affected by the aging process in the males (p < 0.01) but not in the aged females. Electron microscopy revealed more abnormalities which involve the retinal pigment epithelium (RPE) and Bruch’s membrane, outer and inner layers, vascular changes, deposits of amorphous materials, and accumulation of lipids or lipofuscins. Age-related miRNAs, miR-27a-3p (p < 0.01), miR-27b-3p (p < 0.05), and miR-20a-5p (p < 0.05) were significantly up-regulated in aged male mice compared to the controls, whereas miR-20b-5p was significantly down-regulated in aged male (p < 0.05) and female mice (p < 0.05) compared to the respective controls. miR-27a-3p (5.00 fold; p < 0.01) and miR-27b (7.58 fold; p < 0.01) were significantly up-regulated in aged male mice vs. aged female mice, whereas miR-20b-5p (−2.10 fold; p < 0.05) was significantly down-regulated in aged male mice vs. aged female mice. Interestingly, miR-27a-3p, miR-27b-3p, miR-20a-5p, and miR-20b-5p expressions significantly correlated with the thickness of the retinal PS layer (p < 0.01), retinal outer layers (p < 0.01), and Bruch’s membrane (p < 0.01). Our results showed that biological sex can influence the structure and function of the retina upon aging, suggesting that this difference may be underlined by the dysregulation of age-related mi-RNAs.

scholarly journals Changes in Experimental Stroke Outcome across the Life Span

2009 ◽  
Vol 29 (4) ◽  
pp. 792-802 ◽  
Author(s):  
Fudong Liu ◽  
Rongwen Yuan ◽  
Sharon E Benashski ◽  
Louise D McCullough
Keyword(s):  
Life Span ◽  
Cellular Response ◽  
Young Male ◽  
The Elderly ◽  
Young Female ◽  
Artery Occlusion ◽  
Experimental Stroke ◽  
Elderly Age ◽  
Edema Formation ◽  
Female Mice

Acute ischemic stroke is a leading cause of mortality and disability in the elderly. Age is the most important nonmodifiable risk factor for stroke, yet many preclinical models continue to examine only young male animals. It remains unclear how experimental stroke outcomes change with aging and with biologic sex. If sex differences are present, it is not known whether these reflect an intrinsic differing sensitivity to stroke or are secondary to the loss of estrogen with aging. We subjected both young and aging mice of both sexes to middle cerebral artery occlusion (MCAO). Young female mice had smaller strokes compared with age-matched males, an effect that was reversed by ovariectomy. Stroke damage increased with aging in female mice, whereas male mice had decreased damage after MCAO. Blood–brain barrier (BBB) permeability changes are correlated with infarct size. However, aging mice had significantly less edema formation, an effect that was independent of sex and histologic damage. Differences in the cellular response to stroke occur across the life span in both male and female mice. These differences need to be considered when developing relevant therapies for stroke patients, the majority of whom are elderly.

scholarly journals Age and sex dimorphisms contribute to the severity of bleomycin-induced lung injury and fibrosis

2011 ◽  
Vol 301 (4) ◽  
pp. L510-L518 ◽  
Author(s):  
Elizabeth F. Redente ◽  
Kristen M. Jacobsen ◽  
Joshua J. Solomon ◽  
Abigail R. Lara ◽  
Sarah Faubel ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Bronchoalveolar Lavage ◽  
Lung Disease ◽  
Bronchoalveolar Lavage Fluid ◽  
Transforming Growth Factor ◽  
Young Male ◽  
Lavage Fluid ◽  
Male Mice ◽  
Female Mice ◽  
Age And Sex

Fibrotic interstitial pneumonias are more prevalent in males of advancing age, although little is known about the underlying mechanisms. To evaluate the contributions of age and sex to the development of pulmonary fibrosis, we intratracheally instilled young (8–12 wk) and aged (52–54 wk) male and female mice with bleomycin and assessed the development and severity of fibrotic lung disease by measurements of lung collagen levels, static compliance, leukocyte infiltration, and stereological quantification of fibrotic areas in histological sections. We also quantified proinflammatory and profibrotic chemokine and cytokine levels in the bronchoalveolar lavage fluid. Aged male mice developed more severe lung disease, indicated by increased mortality, increased collagen deposition, and neutrophilic alveolitis compared with aged female mice or young mice of either sex. Aged male mice also exhibited increased levels of transforming growth factor-β, IL-17A, and CXCL1 in their bronchoalveolar lavage fluid. Young male mice developed a more fibrotic disease after bleomycin instillation compared with female mice, regardless of age. There was no difference in fibrosis between young and aged female mice. Taken together, these findings suggest that the variables of advanced age and male sex contribute to the severity of pulmonary fibrosis in this model. Our findings also emphasize the importance of stratifying experimental groups on the basis of age and sex in experimental and epidemiological studies of this nature.

Acute and chronic contractile activity-induced adaptations in muscle and mitochondrial function

2009 ◽  
Vol 34 (4) ◽  
pp. 799-800
Author(s):  
Vladimir Ljubicic
Keyword(s):  
Skeletal Muscle ◽  
Oxygen Consumption ◽  
Mitochondrial Function ◽  
Acute Exercise ◽  
Contractile Activity ◽  
Adaptive Plasticity ◽  
Ros Production ◽  
Kinase Signaling ◽  
Mitochondrial Content ◽  
Mitochondrial Volume

Exercise training is a potent stimulus for favourable phenotypic adaptations in muscle, including the induction of mitochondrial biogenesis. Although the occurrence of organelle expansion in response to chronic muscle use is accepted, the cellular events governing this remodeling are undefined. Thus, the purpose of this dissertation was to examine the acute and chronic contractile activity-induced adaptations in skeletal muscle and mitochondrial function in young and old animals. The intracellular signals associated with contractile activity are important for the induction of downstream phenotypic plasticity. In study 1, we investigated the influence of muscle oxygen consumption and reactive oxygen species (ROS) production on kinase signaling. The results demonstrate that mitochondrial content influenced the rate of ROS production in resting muscle. Furthermore, several protein kinases were differentially sensitive to increments in oxygen consumption, and this sensitivity was also related to the muscle mitochondrial volume. In study 2, we further explored the effect of mitochondrial content on the acute contraction-induced kinase signaling in skeletal muscle. We found that mitochondrial content was inversely related to kinase activation in resting skeletal muscle. Moreover, training-induced increases in mitochondrial volume were associated with an attenuated adaptive signaling response subsequent to a single bout of contractions, suggesting a mitochondrially mediated mechanism regulating training-elicited muscle remodeling. The aim of study 3 was to examine the effect of age on the acute exercise-induced signaling response. Skeletal muscle from old animals exhibited pathophysiological properties, including reduced force production, fatigue resistance, mitochondrial content, and ATP-synthesizing ability, all characteristic of aging-associated sarcopenia. This condition was correlated with an attenuated signaling response to acute exercise, which was dependent on muscle mitochondrial content. Study 4 assessed the adaptive plasticity of mitochondria in young and old animals after chronic muscle use. We found that the mitochondria from aged animals were able to adapt favourably to a period of chronic contractile activity, despite an attenuated signaling response after each individual bout of exercise. However, the adaptive plasticity of aged animals was lower than that observed in young animals. These findings underscore the importance of daily physical activity in the maintenance and improvement of health for individuals of all ages.

scholarly journals Toxicity of silver nanoparticles on Endometrial Receptivity in Female Mice

2021 ◽  
Author(s):  
marziyeh ajdary ◽  
Sahar Eghbali ◽  
Vahid Pirhajati Mahabadi ◽  
Fariborz Keyhanfar ◽  
Rajender S Varma
Keyword(s):  
Silver Nanoparticles ◽  
Endometrial Receptivity ◽  
Endometrial Tissue ◽  
The Other ◽  
Male Mice ◽  
Uterine Tissue ◽  
Blood Samples ◽  
Female Mice ◽  
Molecular Tests ◽  
Major Increase

Nanoparticles (NPs) have many toxic effects on fertility and can prevent successful implantation by affecting the maternal uterine tissue. Herein, by deploying thirty female NMRI mice, the effect of silver nanoparticles on the endometrium and implantation has been investigated. Using spherical silver nanoparticles of a diameter of 18-30 nm at doses of 2 and 4 mg/kg, mice in both groups were treated. Then, female mice mated with male mice. Endometrial tissue was extracted 4.5 days later. On the fourth day of pregnancy, the mice were anesthetized and blood samples were taken from the heart; furthermore, endometrial tissue was isolated and used for molecular tests, ICP, and examination of pinopods. The results revealed that the levels of IL6 and IL1β and the accumulation of nanoparticles in endometrial tissue in the group receiving nanoparticles at a dose of 4 mg/kg had a major increase relative to the other two groups (p<0.05); group receiving a dose of 4 mg/kg, exhibited a decrease in pinopods and microvillus compared to the other two groups. According to the results, NPs can reach the endometrium, suggesting that caution should be exercised due to serious exposure to nanoparticles throughout pregnancy.

scholarly journals Heme oxygenase-2 protects against ischemic acute kidney injury: influence of age and sex

2019 ◽  
Vol 317 (3) ◽  
pp. F695-F704 ◽  
Author(s):  
Karl A. Nath ◽  
Vesna D. Garovic ◽  
Joseph P. Grande ◽  
Anthony J. Croatt ◽  
Allan W. Ackerman ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Renal Function ◽  
Heme Oxygenase ◽  
Kidney Injury ◽  
Young Male ◽  
Young Female ◽  
Renal Ischemia ◽  
Sirtuin 1 ◽  
Male Mice ◽  
Phosphorylated Stat3

Heme oxygenase (HO) activity is exhibited by inducible (HO-1) and constitutive (HO-2) proteins. HO-1 protects against ischemic and nephrotoxic acute kidney injury (AKI). We have previously demonstrated that HO-2 protects against heme protein-induced AKI. The present study examined whether HO-2 is protective in ischemic AKI. Renal ischemia was imposed on young and aged HO-2+/+ and HO-2−/− mice. On days 1 and 2 after renal ischemia, there were no significant differences in renal function between young male HO-2+/+ and HO-2−/− mice, between young female HO-2+/+ and HO-2−/− mice, or between aged female HO-2+/+ and HO-2−/− mice. However, in aged male mice, HO-2 deficiency worsened renal function on days 1 and 2 after ischemic AKI, and, on day 2 after ischemia, such deficiency augmented upregulation of injury-related genes and worsened histological injury. Renal HO activity was markedly decreased in unstressed aged male HO-2−/− mice and remained so after ischemia, despite exaggerated HO-1 induction in HO-2−/− mice after ischemia. Such exacerbation of deficiency of HO-2 protein and HO activity may reflect phosphorylated STAT3, as activation of this proinflammatory transcription factor was accentuated early after ischemia in aged male HO-2−/− mice. This exacerbation may not reflect impaired induction of nephroprotectant genes, since the induction of HO-1, sirtuin 1, and β-catenin was accentuated in aged male HO-2−/− mice after ischemia. We conclude that aged male mice are hypersensitive to ischemic AKI and that HO-2 mitigates such sensitivity. We speculate that this protective effect of HO-2 may be mediated, at least in part, by suppression of phosphorylated STAT3-dependent signaling.

scholarly journals Mitochondria-targeted antioxidant supplementation augments acute exercise-induced increases in muscle PGC1α mRNA and improves training-induced increases in peak power independent of mitochondrial content and function in untrained middle-aged men

2021 ◽  
Author(s):  
S. C. Broome ◽  
T. Pham ◽  
A. J. Braakhuis ◽  
R. Narang ◽  
H. W. Wang ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Exercise Training ◽  
Mitochondrial Biogenesis ◽  
High Intensity ◽  
Peak Power ◽  
Acute Exercise ◽  
Mitochondrial Content ◽  
High Intensity Interval ◽  
Exercise Induced ◽  
And Function

ABSTRACTThe role of mitochondrial ROS production and signalling in muscle adaptations to exercise training has not been explored in detail. Here we investigated the effect of supplementation with the mitochondria-targeted antioxidant MitoQ on a) the skeletal muscle mitochondrial and antioxidant gene transcriptional response to acute high-intensity exercise and b) skeletal muscle mitochondrial content and function following exercise training. In a randomised, double-blind, placebo-controlled, parallel design study, 23 untrained men (age: 44 ± 7 years, VO2peak: 39.6 ± 7.9 ml/kg/min) were randomised to receive either MitoQ (20 mg/d) or a placebo for 10 days before completing a bout of high-intensity interval exercise (cycle ergometer, 10 × 60 s at VO2peak workload with 75 s rest). Blood samples and vastus lateralis muscle biopsies were collected before exercise and immediately and 3 hours after exercise. Participants then completed high-intensity interval training (HIIT; 3 sessions per week for 3 weeks) and another blood sample and muscle biopsy were collected. MitoQ supplementation augmented acute exercise-induced increases in skeletal muscle mRNA expression of the major regulator of proteins involved in mitochondrial biogenesis peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-α). Despite this, training-induced increases in skeletal muscle mitochondrial content were unaffected by MitoQ supplementation. HIIT-induced increases in VO2peak and 20 km time trial performance were also unaffected by MitoQ while MitoQ augmented training-induced increases in peak power achieved during the VO2peak test. These data suggest that MitoQ supplementation enhances the effect of training on peak power, which may be related to the augmentation of skeletal muscle PGC1α expression following acute exercise. However, this effect does not appear to be related to an effect of MitoQ supplementation on HIIT-induced mitochondrial biogenesis in skeletal muscle and may therefore be the result of other adaptations mediated by PGC1α.

Sign in / Sign up

Export Citation Format

Share Document